Speaker
Ms
Monsurat Motunrayo Lawal
(UKZN)
Description
**Introduction**
The catalytic mechanism of the Human Immunodeficiency Virus type 1 (HIV-1) protease (PR) is one of the most studied aspartate protease representative. Both experimental and theoretical techniques have been harnessed to provide profound understanding on a number of possible reaction pathways for the catalysis of HIV-1 PR on its natural substrate/ligand. Most of these studies have investigated the stepwise general acid/base mechanism with little attention on a synchronous model in which the proteolytic reaction could occur as a one-step concerted process. Jaskólski et al. first put this proposal forward in 1991 in which the hydrolytic reaction is viewed as a one-step process; the nucleophile (water molecule) and electrophile (an acidic proton) attack the scissile bond in a concerted manner.
**Aim and objective**
Herein, the one-step concerted catalytic mechanism of HIV-1 PR on its natural substrate and a fluoride derivative was studied using density functional theoretical (DFT) method.
**Method**
The reaction was modeled to proceed through the formation of a six-membered ring transition state structure, which was facilitated by a pre-reaction enzyme-substrate complex at B3LYP/6-31+G(d) level of theory using Gaussian 09 program suite. The applied in silico model allows the elucidation activation parameters, kinetics, solvent contributions and quantum chemical properties for this system.
**Result**
Theoretically determined activation free energy of 19 kcal mol-1 obtained was very close to approximately 18 kcal mol-1 reported from experiment. The fluorinated peptide substrate has an activation free energy of 12 kcal mol-1 which is 7 kcal mol-1 lower than natural substrate.
**Implications of result**
This investigation could potentially serve as a basis towards understanding the enzymatic mechanism of homodimeric enzymes and could also guide future design of better HIV-1 PR inhibitors through fluorinating the scissile nitrogen of the natural substrates; an ongoing perspective from our research group.
HPC content
Computational chemistry
Gaussian 09
Primary author
Ms
Monsurat Motunrayo Lawal
(UKZN)
Co-authors
Dr
Bahareh Honarparvar
(UKZN)
Prof.
Hendrik Gert Kruger
(UKZN)
Ms
Zainab Sanusi
(UKZN)
